Process for preparing N-hydroxyformamido-propyl pyrrolidin compounds and intermediates

ABSTRACT

The present invention is directed to a process for preparing intermediates that are useful to prepare certain antibacterial N-formyl hydroxylamine compounds which are peptide deformylase inhibitors. The process makes use α β-lactarn intermediate. Certain optically pure intermediates are also claimed.

This application claims benefit of U.S. Provisional Application No. 60/411,920, filed Sep. 19, 2002, and U.S. Provisional Application No. 60/480,242, filed Jun. 20, 2003 which in their entirety are herein incorporated by reference.

This invention is directed to a process for preparing intermediates that are useful to prepare certain antibacterial N-formyl hydroxylamine compounds.

Peptide deformylase is a metallopeptidase found in prokaryotic organisms such as bacteria. Protein synthesis in prokaryotic organisms begins with N-formyl methionine (fMet). After initiation of protein synthesis, the formyl group is removed by the enzyme peptide deformylase (PDF); this activity is essential for maturation of proteins. It has been shown that PDF is required for bacterial growth (see Chang et al., J. Bacteriol., Vol. 171, pp. 4071-4072 (1989); Meinnel et al., J. Bacteriol, Vol. 176, No. 23, pp. 7387-7390 (1994); Mazel et al., EMBO J., Vol. 13, No. 4, pp. 914-923 (1994)). Since protein synthesis in eukaryotic organisms does not depend on fMet for initiation, agents that will inhibit PDF are attractive candidates for development of new anti-microbial and anti-bacterial drugs.

Co-pending application Ser. No. 10/171,706, filed Jun. 14, 2002 (incorporated herein by reference in its entirety) and WO02/102790, disclose novel N-formyl hydroxylamine compounds that inhibit PDF and are therefore useful as antibacterial agents. The compounds disclosed therein are certain N-[1-oxo-2-alkyl-3-(N-hydroxyformamido)-propyl]-(carbonylamino-aryl or -heteroaryl)-azacyclo₄₋₇alkanes or thiazacyclo₄₋₇alkanes which are described in more detail hereinafter. An improved process has been discovered for preparing intermediates useful for preparing these N-[1-oxo-2-alkyl-3-(N-hydroxyformamido)-propyl]-(carbonylamino-aryl or -heteroaryl)-azacyclo₄₋₇alkanes or thiazacyclo₄₋₇alkanes which makes use of a particular β-lactam intermediate.

The present invention is directed to a novel process for preparing certain intermediates which are useful to prepare certain N-formyl hydroxylamine compounds which are useful for inhibiting bacteria.

More specifically, the present invention is directed to a process for preparing a compound of the formula (VIII)

comprising Step A:

contacting a compound of the formula (I)

with a compound of the formula (II) Y—O—NH₂  (II)

in the presence of a carboxy-activating agent, in a suitable solvent under conditions suitable to form a compound of the formula (III)

followed by Step B:

contacting compound (III) with a compound of the formula (XIII) R′—SO₂—X′  (XIII) in the presence of a base in a suitable solvent, under conditions suitable to form a compound of the formula (IV)

followed by Step C:

contacting compound (IV) with a base in a suitable solvent under conditions suitable to form a compound of the formula (V)

followed by Step D:

contacting compound (V) with a compound of the formula (VI)

in a suitable solvent optionally in the presence of an activator under conditions suitable to form a compound of the formula (VII)

followed by Step E:

contacting compound (VII) with a formylating agent in a suitable solvent under conditions suitable to form compound (VIII);

wherein

-   -   Y is a hydroxy protecting group;     -   each of R₂, R₃, R₄ and R₅ is independently hydrogen or an         aliphatic group, or (R₂ and R₃) and/or (R₄ and R₅) collectively         form a C₄₋₇cycloalkyl;     -   X is —CH₂—, —S—, —CH(OH)—, —CH(OR)—, —CH(SH)—, —CH(SR)—, —CF₂—,         —C═N(OR)— or —CH(F)—;         -   wherein         -   R is alkyl;     -   G is —OH or —O^(⊖)M^(⊕), wherein M is a metal or an ammonium         moiety;     -   R₁ is aryl or heteroaryl;     -   X′ is halo;     -   R′ is alkyl or aryl; and     -   n is 0 to 3, provided that when n is 0, X is —CH₂—.

When the desired product is an N-oxide of an aromatic moiety having a nitrogen heteroatom, e.g., when R₁ is formula (X), (XIa) or (Xb), typically a pyridine derivative, it is necessary to perform an additional step after Step E, i.e., to oxidize the N of the aromatic ring (Step F). Therefore, the present invention includes Step F which comprises contacting the compound of formula (VIII), wherein R₁ is heteroaryl having an N heteroatom, with an oxidizing agent to form the corresponding N-oxide derivative.

In addition to the above process comprising Steps A through E or F, the present invention is directed to each of the steps individually, and to any two or more sequential steps.

DETAILED DESCRIPTION OF THE INVENTION

In particular, the present invention provides a process for preparing intermediates useful in the preparation of a N-[1-oxo-2-alkyl-3-(N-hydroxyformamido)-propyl]-(carbonylamino-aryl or -heteroaryl)-azacyclo₄₋₇alkane or thiazacyclo₄₋₇alkane, e.g., a compound of formula (IX)

wherein R₁, R₂, R₃, R₄, R₅, X and n are as defined above.

To convert the compound of formula (VIII) to the compound of formula (IX), the hydroxy protecting group is removed using conventional hydrogenolysis techniques known in the art, e.g., by contacting the compound of formula (VIII) with a palladium catalyst, such as Pd/BaSO₄.

The R₁ moiety can be a heteroaryl, e.g., an azacyclo₄₋₇alkane, a thiazacyclo₄₋₇alkane or an imidazacyclo₄₋₇alkane. Specific examples of R₁ moieties in the compounds disclosed herein are heteroaryls of formula (X)

wherein each of R₆, R₇, R₈ and R₉, independently, is hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, acyl, acyloxy, SCN, halogen, cyano, nitro, thioalkoxy, phenyl, heteroalkylaryl, alkylsulfonyl or formyl.

A more specific R₁ moiety is a heteroaryl of formula (XIa)

wherein R₆, R₇, R₈ and R₉ are as defined above for formula (X), e.g.,

-   -   wherein         -   a) R₆ is nitro, alkyl, substituted alkyl, phenyl, hydroxy,             formyl, heteroalkylaryl, alkoxy, acyl or acyloxy; preferably             alkyl, especially C₁₋₇alkyl; hydroxyl; or alkoxy, especially             a C₁₋₇alkoxy; and             -   R₇, R₈ and R₉ are hydrogen; or         -   b) R₆, R₈ and R₉ are hydrogen; and             -   R₇ is alkyl, substituted alkyl, phenyl, halogen, alkoxy                 or cyano, preferably alkyl, especially C₁₋₇alkyl;                 substituted alkyl, especially substituted C₁₋₇alkyl,                 such as —CF₃; or alkoxy, especially C₁₋₇alkoxy; or         -   c) R₆, R₇ and R₉ are hydrogen; and             -   R₈ is alkyl, substituted alkyl, halogen, nitro, cyano,                 thioalkoxy, acyloxy, phenyl, alkylsulfonyl or                 carboxyalkyl, preferably alkyl, especially C₁₋₇alkyl;                 substituted alkyl, especially —CF₃; halogen such as                 chloro, bromo or fluoro; or carboxyalkyl; or         -   d) R₆, R₇ and R₈ are hydrogen; and             -   R₉ is alkyl, halogen or hydroxy; or         -   e) R₇ and R₉ are hydrogen; and             -   each of R₆ and R₈, independently, is halogen, alkyl,                 substituted alkyl, phenyl or cyano; or         -   f) Each of R₇ and R₉ is alkyl or substituted alkyl; and             -   R₆ and R₈ are hydrogen; or         -   g) R₆ and R₉ are hydrogen;             -   R₇ is alkyl or substituted alkyl; and             -   R₈ is nitro; or         -   h) R₈ and R₉ are hydrogen;             -   R₆ is cyano; and             -   R₇ is alkoxy; or         -   i) R₇ and R₈ are hydrogen; and             -   R₆ is alkyl, substituted alkyl, alkoxy or SCN; and             -   R₉ is alkyl or substituted alkyl; or         -   j) R₆ and R₇ are hydrogen;             -   R₈ is nitro or halogen; and             -   R₉ is alkyl or substituted alkyl; or         -   k) R₆, R₇, R₈ and R₉ are hydrogen; or,         -   l) R₆ and R₇ together with the carbon atoms to which they             are attached form a phenyl group, preferably substituted             with hydroxy; and             -   R₈ and R₉ are hydrogen; or         -   m) R₆ and R₇ are hydrogen; and             -   R₈ and R₉ together with the carbon atoms to which they                 are attached form a phenyl group; or         -   n) n is 0; or         -   o) n is 0;             -   each of R₆, R₇, R₈ and R₉, independently, is hydrogen,                 alkyl or halogen; and             -   more particularly, R₆, R₇, R₈ and R₉ are hydrogen; or         -   p) n is 0;             -   R₆, R₈ and R₉ are hydrogen; and             -   R₇ is alkyl; or         -   q) n is 0;             -   R₆, R₇ and R₉ are hydrogen; and             -   R₈ is alkyl or halogen.

In another embodiment, R₁ is of formula (Xb)

wherein

-   -   R₆, R₇, R₈ and R₉ are as defined above for formula (X); in         particular, R₇ and R₈ together with the carbon atoms to which         they are attached form a phenyl group; and     -   R₆ and R₉ are hydrogen.

In yet another embodiment, the R₁ is of formula (XI)

wherein each of R₆, R₇, R₈ and R₉ independently is hydrogen, alkyl, substituted alkyl, phenyl, halogen, hydroxy or alkoxy, e.g.,

-   -   wherein         -   a) R₆ and R₈ are hydrogen;             -   R₉ is hydrogen or alkyl; and             -   R₇ is alkyl, substituted alkyl or phenyl; or         -   b) R₆, R₇ and R₉ are hydrogen; and             -   R₈ is halogen, alkyl or substituted alkyl; or         -   c) R₇, R₈ and R₉ are hydrogen; and             -   R₆ is hydroxy.

In a particularly useful embodiment the heteroaryl is of the formula (XIa)

wherein R₆, R₇, R₈ and R₉ are as defined above for formula (XI), in particular where R₆, R₇, and R₉ are hydrogen and R₈ is fluoro.

In another embodiment, R₁ is an unsubstituted phenyl or the phenyl is substituted with alkoxy, e.g., methoxy; or aryloxy, e.g., phenoxy.

In another embodiment, the R₁ is of formula (XII)

wherein each of R₁₀ and R₁₁, independently, is hydrogen or halogen. In particular, R₁₀ and R₁₁ are both either hydrogen or both halogen.

In the compound of formula (I), M is a metal, typically a mono- or di-valent metal or an ammonium moiety. Typical metals include Mg, Ca, Na, K Li and the like. The ammonium moiety is of the formula

wherein R″ is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl.

The ammonium moiety can be racemic or chiral. An example of an ammonium moiety is R-α-methylbenzylammonium. Examples of R″ groups include hydrogen, methyl, ethyl, propyl, butyl, phenyl, benzyl, methylbenzyl and the like.

Unless otherwise stated, the following terms as used in the specification have the following meaning.

The term “cycloalkane” or “cycloalkyl” contains from 3- to 7-ring carbon atoms, and is, e.g., cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term “azacyclo₄₋₇alkane” contains 1-ring heteroatom which is a nitrogen. It contains from 4-7, and especially 4- or 5-ring atoms including the heteroatom.

The term “thiazacyclo₄₋₇alkane” contains 2-ring heteroatoms, nitrogen and sulfur. It contains from 4-7, and especially 5-ring atoms including the heteroatoms.

The term “imidazacyclo₄₋₇alkane” contains 2-ring heteroatoms which are both nitrogen. It contains from 4-7, and especially 5-ring atoms including the heteroatoms.

The term “aliphatic group” refers to saturated or unsaturated aliphatic groups, such as alkyl, alkenyl or alkynyl, cycloalkyl or substituted alkyl including straight-chain, branched-chain and cyclic groups having from 1-10 carbons atoms. Preferably “alkyl” or “alk”, whenever it occurs, is a saturated aliphatic group or cycloalkyl, more preferably C₁₋₇alkyl, particularly C₁₋₄alkyl. Examples of “alkyl” or “alk” include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, cyclopropyl and especially n-butyl.

The term “substituted alkyl” refers to an alkyl group that is substituted with one or more substituents preferably 1-3 substituents including but not limited to, substituents, such as halogen, lower alkoxy, hydroxy, mercapto, carboxy, cycloalkyl, aryl, heteroaryl and the like. Examples of substituted alkyl groups include, but are not limited to, —CF₃, —CF₂—CF₃, hydroxymethyl, 1- or 2-hydroxyethyl, methoxymethyl, 1- or 2-ethoxyethyl, carboxymethyl, 1- or 2-carboxyethyl and the like.

The term “aryl” or “Ar” refers to an aromatic carbocyclic group of 6-14 carbon atoms having a single ring including, but not limited to, groups, such as phenyl; or multiple condensed rings including, but not limited to, groups, such as naphthyl or anthryl; and is especially phenyl.

The term “heteroaryl” or “HetAr” refers to a 4- to 7-membered, monocyclic aromatic heterocycle or a bicycle that is composed of a 4- to 7-membered, monocyclic aromatic heterocycle and a fused-on benzene ring. The heteroaryl has at least one hetero atom, preferably one or two heteroatoms including, but not limited to, heteroatoms, such as N, O and S, within the ring. A preferred heteroaryl group is pyridinyl, pyrimidinyl or benzdioxolanyl.

The aryl or heteroaryl may be unsubstituted or substituted by one or more substituents including, but not limited to, C₁₋₇alkyl, particularly C₁₋₄alkyl, such as methyl, hydroxy, alkoxy, acyl, acyloxy, SCN, halogen, cyano, nitro, thioalkoxy, phenyl, heteroalkylaryl, alkylsulfonyl and formyl.

The term “carbonylamine”, as used herein, refers to a —NHC(O)— group wherein the amino portion of the group is linked to the aryl/heteroaryl and the carbonyl portion of the group is linked to the azacyclo₄₋₇alkane, thiazacyclo₄₋₇alkane or imidazacyclo₄₋₇alkane.

The term “heteroalkyl” refers to saturated or unsaturated C₁₋₁₀alkyl as defined above, and especially C₁₋₄heteroalkyl which contain one or more heteroatoms, as part of the main, branched or cyclic chains in the group. Heteroatoms may independently be selected from the group consisting of —NR—, where R is hydrogen or alkyl, —S—, —O— and —P—; preferably —NR—, where R is hydrogen or alkyl; and/or —O—. Heteroalkyl groups may be attached to the remainder of the molecule either at a heteroatom (if a valence is available) or at a carbon atom. Examples of heteroalkyl groups include, but are not limited to, groups, such as —O—CH₃, —CH₂—O—CH₃, —CH₂—CH₂—O—CH₃, —S—CH₂—CH₂—CH₃, —CH₂—CH(CH₃)—S—CH₃ and —CH₂—CH₂—NH—CH₂—CH₂—.

The heteroalkyl group may be unsubstituted or substituted with one or more substituents, preferably 1-3 substituents including, but not limited to, alkyl, halogen, alkoxy, hydroxyl, mercapto, carboxy and especially phenyl. The heteroatom(s) as well as the carbon atoms of the group may be substituted. The heteroatom(s) may also be in oxidized form.

The term “alkoxy”, as used herein, refers to a C₁₋₁₀alkyl linked to an oxygen atom, or preferably C₁₋₇alkoxy, more preferably C₁₋₄alkoxy. Examples of alkoxy groups include, but are not limited to, groups such as methoxy, ethoxy, h-butoxy, tert-butoxy and allyloxy.

The term “acyl”, as used herein, refers to the group —(O)CR, where R is alkyl, especially C₁₋₇alkyl, such as methyl. Examples of acyl groups include, but are not limited to, acetyl, propanoyl and butanoyl.

The term “acyloxy”, as used herein, refers to the group —OC(O)R, wherein R is hydrogen, alkyl, especially C₁₋₇alkyl, such as methyl or ethyl, or phenyl or substituted alkyl as defined above.

The term “alkoxycarbonyl”, as used herein, refers to the group —COOR, wherein R is alkyl, especially C₁₋₇alkyl, such as methyl or ethyl.

The term “halogen” or “halo”, as used herein, refers to chlorine, bromine, fluorine, iodine and is especially fluorine.

The term “thioalkoxy”, as used herein, means a group —SR, where R is an alkyl as defined above, e.g., methylthio, ethylthio, propylthio, butylthio and the like.

The term “heteroalkylaryl”, as used herein, means a heteroalkyl group, e.g., —O—CH₂— substituted with an aryl group, especially phenyl. The phenyl group itself may also be substituted with one or more substituents, such as halogen, especially fluoro and chloro; and alkoxy such as methoxy.

The term “alkylsulfony”, as used herein, means a group —SO₂R, wherein R is alkyl especially C₁₋₇alkyl, such as methyl sulfonyl.

“Protecting group” refers to a chemical group that exhibits the following characteristics: 1) reacts selectively with the desired functionality in good yield to give a protected substrate that is stable to the projected reactions for which protection is desired, 2) is selectively removable from the protected substrate to yield the desired functionality; and 3) is removable in good yield by reagents compatible with the other functional group(s) present or generated in such projected reactions. Examples of suitable protecting groups may be found in Greene et al., “Protective Groups in Organic Synthesis”, 3^(rd) Ed., John Wiley & Sons Inc., NY (1999). Preferred hydroxy protecting groups include benzyl, Fmoc, TBDMS, photolabile protecting groups, such as Nvom, Mom and Mem. Other preferred protecting groups include NPEOC and NPEOM.

It will be appreciated that the compounds disclosed herein may exist in the form of optical isomers, racemates or diastereoisomers. In particular, in the compounds disclosed herein where R₄ and R₅ are different, the carbon atom to which the R₄ and R₅ groups are bonded is a chiral center and such compounds can exist in the R, S or racemic forms. It is preferred that the process of the invention prepares the R optically pure form. By “optically pure” is meant that the enantiomeric purity is greater than 50%, preferably greater than 80%, more preferably greater than 90%, and most preferably greater than 95%. The optically pure R isomer of compound (I) can be used, in which case all subsequent compounds in the synthesis will remain in the R optically pure form, with respect to the same chiral carbon atom. If an optically pure compound is used as the starting material, purification from the undesired diastereomer can be avoided at later steps. Such R form of compound (I) is represented below:

wherein R₂, R₃, R₄ and R₅ are as defined above. The optically pure form of compound (I) is novel provided that when either R₄ or R₅ is hydrogen, the other substituent, i.e., R₄ or R₅ is not hydrogen or methyl. In a particular embodiment of the novel compound of formula (I), R₅ is hydrogen and R₄ is C₂₋₁₀alkyl, in a more particular embodiment C₂₋₇alkyl, and in a even more particular embodiment C₄alkyl.

In a further embodiment an optically pure compound of formula (I) t R₂, R₃, and R₅ are hydrogen and R₄ is alkyl; such a compound has the structure (Ia):

Another embodiment in compound (I) is where R₄ is n-butyl, where such compound has the structure (Ib)

Another embodiment is where R₂, R₃ and R₅ are hydrogen and R₄ is n-butyl; such compound has the structure (Ic):

More particular examples of the optically pure compound of formula (I) are as follows:

Alternatively, the racemate form of compound (I) can be used and then the R form can be resolved at a later step and the R form used for subsequent steps. For example, the compound formed after opening the β-lactam ring, i.e., compound (VII), the product of Step D, can be resolved into its RS and SS diastereomers and only the RS diastereomer used for subsequent steps. The RS diastereomer of compound (VII) is depicted below:

wherein R₂, R₃, R₄ R₅ Y, X, R₁ and n are as defined above, provided that R₄ and R₅ are different.

The diastereoisomers are resolved using standard techniques known in the art, for example, using silica gel column chromatography and an ethyl acetate/hexane solvent system (see, e.g., the methods taught in Chapter 4 of “Advanced Organic Chemistry”, 5^(th) edition, J. March, John Wiley and Sons, NY (2001)).

In the compounds disclosed herein, the following significances are specific embodiments individually or in any sub-combination:

-   1. R₁ is a heteroaryl of formula (IIa), wherein R₆, R₇ and R₉ are     hydrogen and R₈ is methyl or trifluoromethyl; or R₆, R₇ and R₈ are     hydrogen and R₉ is fluoro; or R₆, R₈ and R₉ are hydrogen and R₇ is     ethyl or methoxy; or R₇, R₈ and R₉ are hydrogen and R₆ is hydroxy;     or R₇ and R₈ are hydrogen, R₆ is methoxy and R₉ is methyl; or R₁ is     a heteroaryl of formula (IIIa), wherein R₆, R₇ and R₉ are hydrogen     and R₈ is fluoro or trifluoromethyl; or R₆, R₈ and R₉ are hydrogen     and R₇ is ethyl; preferably R₁ is a heteroaryl of formula (IIa),     wherein R₆, R₈ and R₉ are hydrogen and R₇ is ethyl or a heteroaryl     of formula (IIIa), wherein R₆, R₇ and R₉ are hydrogen and R₈ is     fluoro. -   2. X is —CH₂—, —CH(OH)—, —CH(OR)—, —CF₂— or —CH(F)—, preferably X is     —CH₂—; -   3. R₄ is alkyl, preferably C₁₋₇alkyl, such as n-butyl; -   4. n is 1.

Temperature and pressure are not known to be critical for carrying out any of the steps of the invention, i.e., Steps A through E. Generally, for any of the steps, a temperature of about −10° C. to about 150° C., preferably about 0° C. to about 80° C., is typically employed. Typically about atmospheric pressure is used for convenience; however, variations to atmospheric pressure are not known to be detrimental. Oxygen is not known to be detrimental to the process, therefore for convenience the various steps can be performed under ambient air, although an inert atmosphere, such as nitrogen or argon, can be used if desired. For convenience equimolar amounts of reactants are typically used; however molar ratios can vary from about 1 to 2 equivalents, relative to the other reactant. The pH for the various steps is typically about 2 to about 12. The solvent used for the various steps are typically organic solvents, although in some situations aqueous/organic solvents can be used. Examples of suitable solvents include dioxane; mtehylene chloride; dichloromethane; toluene, acetone; methyl ethyl ketone; THF; isopropyl acetate; DMF; alcohols, especially higher branched alcohols, such as t-butanol; and the like.

For Step A, a typical temperature is about 0° C. to about 50° C., preferably about 5° C. to about 35° C.; and a typical reaction time is about 1 hour to about 10 hours, preferably about 2 hours to about 5 hours. A pH of about 2 to about 7, preferably about 3 to about 5, more preferably about 4, is typically employed. The carboxy-activating agent can be for example, DCC, CDMT, EDCl and the like. The amount of carboxy-activating agent employed is typically about 0.5 to about 2 molar equivalents relative to compound (I). The solvent is water or a mixture of water and one or more organic solvents, such as THF, dioxane, alcohols, such as methanol, ethanol and the like. Specific examples of solvents include THF/water and water. In the event that an ammonium salt of compound (I) is used in the process, the salt will be dissolved in water containing at least a molar equivalent amount of base, such as alkaline metal hydroxide, such as NaOH and KOH; the base is added to liberate the free amine which is extracted into the organic phase, the aqueous phase is used for the coupling reaction.

For Step B, a typical temperature is about −20° C. to about 25° C., more typically about −5° C. to about 5° C.; and a typical reaction time is about 1 hour to about 2 hours, more typically about 2 hours to about 5 hours. For Step B, an alcoholic solvent should not be used. For reactant (XIII), X′ is preferably chloro and R′ is preferably lower alkyl or phenyl, with CH₃SO₂CI and tosyl chloride being most typical. The pH for Step B is basic and is typically about 9 to about 10. The base used for Step B can be any conventional base known in the art that will activate the hydroxy group of compound (III), and such base will be used in a hydroxyl-activating amount which is at least about 1 molar equivalent relative to compound (III). The base can also act as solvent in which case it will be present in a solvating amount which is in excess of the above amount. Examples of bases that can be employed include pyridine; DMAP; a trialkylamine, e.g., trimethylamine; resin-bound bases; Hunig bases; and the like. A particular solvent is pyridine, THF or EtOAc.

For cyclization Step C, a typical temperature is about 20° C. to about 150° C., more typically about 40° C. to about 80° C.; and a typical reaction time is about 1 hour to about 20 hours, more typically about 2 hours to about 4 hours. The pH for Step C is basic, typically, about 8 to about 12. The base used in Step C can be any base known in the art that is capable of de-protonating the amide group of compound (IV). Examples of suitable bases include inorganic or organic bases, such as potassium carbonate; lithium carbonate; sodium carbonate; lithium bicarbonate; sodium bicarbonate; alkyl lithium, e.g., butyl lithium; and the like. The amount of base employed is a de-protonating amount which is typically in molar excess to the amount of compound (IV), e.g., about 1-5 equivalents relative to compound (IV). For certain solvents, such as THF, dioxane, dimethoxyethane and the like, it may be necessary to use a catalytic amount of a phase transfer catalyst, such as trialkylarylammonium salt or a tetraalkylammonium salt, e.g., tetrabutylammonium chloride or tetrabutylammonium bromide. The examples of solvents are ketones, such as acetone or methylethylketone.

For Step D, a typical temperature is about 30° C. to about 150° C., more typically about 60° C. to about 80° C.; and a typical reaction time is about 3 hours to about 20 hours, more typically about 5 hours to about 10 hours. The pH for Step D is typically about 5 to about 11. The activator for Step D is a compound which protonates the β-lactam keto oxygen; such activators include, e.g., mild (weak) organic acids, such as branched or unbranched carboxylic acids, e.g., 2-ethylhexanoic acid, acetic acid, isobutryic acid and the like. If an aqueous alcoholic solvent is used an activator is not needed; examples ofd aqueous alcoholic solvents include MeOH.H₂O, EtOH.H₂O and the like. If an activator is used a typical solvent is THF, dioxane or dimethoxyethane. If an activator is used it is used in an protonating amount which is typically about 0.1 molar equivalents to about 2 molar equivalents relative to compound (V).

For Step E, a typical temperature is about −30° C. to about 50° C., more typically about 0° C. to about 25° C.; and a typical reaction time is about 10 minutes to about 5 hours, more typically about 20 minutes to about 1 hour. The pH for Step E is not critical and can vary considerably. For Step E the solvent should not be an alcoholic solvent. The formylating agent can be, for example, HCO₂H/Ac₂O, trifluoroethylformate, and the like, and is present in a formylating amount which is typically about 1 molar equivalent to about 2 molar equivalents relative to compound (VII). A typical solvent is EtOAc, isopropylacetate, t-butylacetate or THF.

For Step F, a typical temperature is about 10° C. to about 35° C., more typically about 20° C. to about 22° C.; and a typical reaction time is about 60 minutes to about 18 hours, more typically about 4 hours to about 8 hours. The pH for Step F is typically about 4 to about 8. The solvent for Step F is typically an organic solvent, i.e., ethyl acetate, iso-propyl acetate, methylene chloride, and the like. The oxidizing agent can be a conventional agent known in the art, e.g., as disclosed in March, “Advanced Organic Chemistry”, Chapter 19, 5^(th) edition, Wiley Interscience, NY, incorporated herein by reference. Typical oxidizing agents include urea/hydrogen peroxide with phthalic anhydride; magnesium monoperoxyphthalate (MMPP); MCPBA, Oxone (available from Aldrich), and the like.

Insofar as the production of starting materials is not particularly described, the compounds are known or may be prepared analogously to methods known in the art or as disclosed in the examples hereinafter.

The following abbreviations are used:

-   Ac=acetyl -   CDMT=chlorodimethoxy triazine -   DIEA=diisopropylethylamine -   DCC=dicyclohexylcarbodimide -   DMAP=dimethylaminopyridine -   DMF=dimethylformamide -   EDCl=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride -   2-EHA=2-ethylhexanoic acid -   EtOAc=ethyl acetate -   EtOH=ethanol -   Fmoc=9-fluorenylmethyl-oxycarbonyl -   HPLC=high performance liquid chromatography -   MeOH=methanol -   Mom=methoxy methyl ether -   Mem=methoxy ethoxy methyl ether -   NPEOC=4-nitrophenethyloxycarbonyl -   NPEOM=4-nitrophenethyloxy-methyloxycarbonyl -   Nvom=nitroveratryl oxymethyl ether -   TBDMS=t-butyidimethylsilyl, -   TMSCI=trimethylsilyl chloride -   RT=room temperature -   THF=tetrahydrofuran

The following examples illustrate the process of the invention but should not be interpreted as a limitation thereon:

Product numbers in the following examples refer to reaction scheme I depicted immediately above.

Product A3

A flask was charged with 2.80 g (19.2 mmol) of A1, 80 mL of THF, 20 mL of water, and 4.73 g (38.4 mmol) of A2. The resulting solution was stirred at RT and the pH of the solution was adjusted to 4.2-4.5 with 2N HCl acid solution.

5.52 g (28.8 mmol) of EDCl was added in three portions (2.12 g, 2.26 g, 1.14 g) within 15 minutes. The resulting solution was stirred at RT for 2 hours, and the pH of the solution was adjusted to 4.2-4.5 during the reaction. The progress of the reaction was monitored by HPLC. After the reaction was completed, THF was evaporated under reduced pressure, and the residue was extracted with 3×70 mL of ethyl acetate and the combined organic phase was washed sequentially with 2×50 mL of 10% citric acid solution, 50 mL of water, 2×50 mL of 5% sodium bicarbonate solution and 50 mL brine dried over MgSO₄. The evaporation of organic solvent afforded 2.4 g of A3 (94% yield).

Product A4

A flask was charged with 7.53 g (30 mmol) of A3 and 30 mL of pyridine. The resulting solution was cooled to 0±2° C. with ice-salt bath. Then, 2.78 mL (36 mmol) of methanesulfonyl chloride was slowly added and maintained the temperature at 0±2° C. for 1.5 hours. After the reaction monitored by HPLC was completed, the mixture was poured into cold 120 mL of 1N HCl acid, and extracted with 2×100 mL of ethyl acetate. The organic phase was washed sequentially with 2×70 mL of 1N HCl acid until the aqueous solution was acidic, 100 mL of saturated sodium bicarbonate solution, 100 mL of brine and dried over MgSO₄. The evaporation of organic solvent gave 9.87 g of A4 (˜100% yield).

Product A5

A flask was charged with 16.07 g (116 mmol) of potassium carbonate (powdered), 631 mL of acetone. The suspension was heated to reflux. Then, 12.49 g (38 mmol) of A4 in 91 mL of acetone was slowly added (30 minutes). The resulting mixture was stirred at reflux for 1 hour. After the reaction monitored by HPLC was completed, the suspension was filtered through celite, and washed with 200 mL of ethyl acetate. The organic solvent was concentrated and diluted with 400 mL of ethyl acetate and washed with 100 mL of 1N HCl acid, 100 mL of saturated sodium bicarbonate solution, 100 mL of brine and dried over MgSO₄. The concentration of organic solvent under reduced pressure afforded 7.96 g of A5 (liquid, 90% yield).

When the A5 is racemic, attacking with chiral A6 results in two diastereomers A7 and A7′ They can be separated by silica gel column using EtOAc and hexanes (1:1) as eluent system. A7 was the second fraction from column and it was identified by comparing with the authentic sample from the other approach.

There are several methods to open the β-lactam ring in A5. The results for opening the lactam ring are summarized in Table 1.

TABLE 1 Reaction Conditions and Results for Coupling A5 and A6 Temp. Time A5 A6 Solventy Additives (° C.) (h) Remarks 5 mmol 6 mmol MeOH (25 ml) 22 1 None 65 1 None  0.1 mL - 2 EHA  66 1 Non 1 mL - H2O 22 15 None 1 mL - H2O 70 2 None MeOH (5 mL 2 mL - H2O 82 17 100% conversion 5 mmol 7.5 mmol Toluene 115 3 None   0.5 mL - TMSCI 116 4 3% conversion    1 mL - 2EHA 115 3 100% conversion one bypd. 5 mmol 6 mmol THF 0.2 mL - 2EHA  70 7 98% conversion Product A7 and A7′

A flask was charged with 1.165 g (5 mmol) of A5, 10 mL of THF, 1.24 g (6 mmol) of A6 and 0.2 mL (1.25 mmol) of 2-ethyl hexanoic acid. The resulting solution was heated to reflux (70° C.) for 7 hours, and the reaction was monitored by HPLC. THF was evaporated and the residue was dissolved in 100 mL of ethyl acetate. The organic layer was washed sequentially with 25 mL of water, 25 mL of saturated sodium bicarbonate, 25 mL of brine and dried over MgSO₄. The concentration of organic solvent gave oil which was further purified by column separation on silica gel to give 0.95 g of A7 and 0.85 g of A7′ (84% total yield).

Product A8

A small flask was charged with 0.35 g (3.43 mmol) of acetic anhydride, and cooled to <10° C. Then, 0.50 g (10.8 mmol) of formic acid (96%) was slowly added to the it (25 minutes). After the addition, the solution was warmed to RT and stirred at this temperature for 30 minutes.

A flask was charged with 0.62 g (1.40 mmol) of A7 and 5 mL of ethyl acetate. The solution was cooled to −3 to 0° C. with ice-salt bath. Then, the solution prepared from above procedure was slowly added (30 minutes). After addition, the reaction was completed (monitored by HPLC). The solution was diluted with 100 mL of ethyl acetate, and washed sequentially with 25 mL of water, 2×25 mL of saturated sodium bicarbonate, 25 mL of brine and dried over MgSO₄. The organic solvent was evaporated to give 0.61 g of A8.

The lactam ring can also be opened by a base, such as lithium hydroxide. As depicted below, the opening ring product was obtained in 91.5% yield with high purity after work-up.

A flask was charged with 1.165 g (5 mmol) of A5, 15 mL of THF, 5 mL of methanol. The resulting solution was cooled to 0° C. Then, 0.25 g of lithium hydroxide monohydrate in 5 mL of water was added. The solution was stirred and allowed to warm to 22° C. for 18 hours. After the reaction monitored by HPLC was completed, the pH of the mixture was adjusted to 2 with 2N HCl acid. The organic solvents were removed, and the residue was extracted with 2×50 mL of ethyl acetate, and washed with 2×30 mL of brine and dried over MgSO₄. The evaporation the organic solvent gave 1.15 g of desired product in 91.5% yield with high purity.

The product numbers in the following examples refer to Reaction Scheme II depicted immediately above.

Compound C3

From (2R)-2-(hydroxymethyl)hexanoic acid:

A 5 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer and nitrogen inlet-outlet, is charged with 102.39 g of (2R)-2-(hydroxymethyl)hexanoic acid, 123.0 g of O-benzylhydroxylamine hydrochloride and 2.25 L of water. Adjust the pH by adding one equivalent of NaOH to a pH of 4-5. Stir the reaction mixture at 18° C.±3° C. (external temperature: 15-18° C.) for 30 minutes to give a cloudy solution. Add 161.3 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCl) over a period of 60 minutes in 6 portions, while maintaining the internal temperature at 18° C.±3° C. (external temperature: 10° C.±3° C.). Wash the funnel once with 50 mL of water. Stir the thick suspension at 20° C.±3° C. for 2 hours. Filter the solids through a polypropylene filter cloth and a Büchner funnel then wash the flask and filter cake once with 0.5 L of water. Air-dry the cake at 20° C.±3° C. (house vacuum) for 2 hours, then dry the wet cake (˜265 g weight) at 65° C.±3° C. (15 mbar) for 24 hours to give 162 g of (2R)-2-(hydroxymethyl)-N-(phenylmethoxy)hexanamide (C3) as a white solid in 95% yield. m.p. 100-102° C.; [α]_(D) ²⁵=+0.556 (c, 1.0, MeOH).

From Sodium Salt:

A 5 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer and nitrogen inlet-outlet, is charged with 117.8 g of (2R)-2-(hydroxymethyl)hexanoic acid sodium salt, 123.0 g of O-benzylhydroxylamine hydrochloride, and 2.25 L of water.

Stir the reaction mixture at 18° C.±3° C. (external temperature: 15-18° C.) for 30 minutes to give a cloudy solution. Add 161.3 g of 1-[3-(dimethylamino)propyl]-3-EDCl over a period of 60 minutes in 6 portions, while maintaining the internal temperature at 18° C.±3° C. (external temperature: 10° C.±3° C.). Wash the funnel once with 50 mL of water. Stir the thick suspension at 20° C.±3° C. for 2 hours. Filter the solids through a polypropylene filter cloth and a Büchner funnel then wash the flask and filter cake once with 0.5 L of water. Air-dry the cake at 20° C.±3° C. (house vacuum) for 2 hours, then dry the wet cake (˜265 g weight) at 65° C.±3° C. (15 mbar) for 24 hours to give 162 g of (2R)-2-(hydroxymethyl)-N-(phenylmethoxy)hexanamide (C3) as a white solid in 95% yield. m.p. 100-102° C.; [α]_(D) ²⁵=+0.556 (c, 1.0, MeOH).

From R-α-methylbenzylammonium Salt:

A 12 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer and nitrogen inlet-outlet, is charged with 300 g of (2R)-2-(hydroxymethyl)hexanoic acid R-α-methylbenzylammonium salt and 1.12 L of water and 2.2 L of tert-butyl methyl ether. Cool the suspension to an internal temperature at 18-22° C. over a period of 20 minutes and add a solution of 94.24 g aqueous NaOH (50% w/w). Stir the solution for 30 minutes and separate layers. Wash the aqueous layer with 2.2 L of tert-butyl Methyl ether. Separate layers and save the aqueous layer containing the (2R)-2-(hydroxymethyl)hexanoic acid sodium salt and proceed as mentioned in Example 1 to get compound 3 in 91% yield; m.p. 100-102° C.; [α]_(D) ²⁵=+0.556 (c, 1.0, MeOH).

Alternatively the corresponding potassium, lithium or calcium salts of (2R)-2-(hydroxymethyl)hexanoic acid were also used in this step as described in Example 2.

In addition, any other ammonium salts of (2R)-2-(hydroxymethyl)hexanoic acid can be used after removing the amine component as described in Example 3.

Compounds C3→C4

A flask was charged with 7.53 g (30 mmol) of C3, and 15 mL of pyridine. The resulting solution was cooled to 0±4° C. with ice-salt bath. Then, 2.78 mL (42 mmol) of methanesulfonyl chloride was slowly added and maintained temperature at 0±4° C. for 2 hours. After the reaction monitored by HPLC was completed, the mixture was quenched by slow addition of 95 mL of 2N HCl at −5±5° C., then warmed to RT and stirred at this temperature for 2 hours. The solids were filtered and washed with water (30 mL), dried in an oven at 50° C. for 14 hours to give 9.86 g of C4 (˜100% yield); [α]_(D) ²⁵=+5.901 (c, 1.0, MeOH).

Compound C5

A flask was charged with 3.86 (27.8 mmol) of potassium carbonate, 50 mL of THF and 0.3 g of tetrabutylammonium bromide. The suspension was heated to 40° C. and stirred at this temperature for 30 minutes. Then, 3.0 g (9.1 mmol) of C4 was added in one portion. The mixture was heated to 60° C. and stirred at this temperature for 1 hour. After the reaction, is completed as monitored by HPLC, the solid was filtered and washed with 20 mL of THF. The organic solvent was concentrated to 8.58 mL/g (THF/C5) for the following step without further purification. The pure C5: [α]_(D) ²⁵=+24.63 (c, 1.0, MeOH).

Compound C6

A flask was charged with 2.12 g (9.1 mmol) of C5 from previous experiment in 20 mL of THF, 2.26 g (10.9 mmol) of Y5a and 0.8 mL of 2-ethyl hexanoic acid. The resulting solution was heated to reflux (70° C.) for 8 hours, and the reaction was monitored by HPLC. THF was evaporated and the residue was dissolved in 50 mL of ethyl acetate.

The organic layer was washed sequentially with 20 mL of water 2×20 mL of 1 N HCl solution, 20 mL of saturated sodium bicarbonate and 20 mL of brine. The concentration of organic solvent gave 3.78 g of C6 (94% yield) in 21 mL of ethyl acetate which was used for the following step. The pure C6: [α]_(D) ²⁵=−74.43 (c, 1.0, MeOH).

Step C6+C7→C8

A flask was charged with 22.6 g (0.22 mole) of acetic anhydride, and cooled to <10° C. Then, 32.3 g (0.674 mole) of formic acid (96%) was slowly added to the flask (25 minutes), and maintained the temperature between 5-10° C. After addition, the solution was warmed to RT and stirred at this temperature for 30 minutes.

A flask was charged with 36 g (81.4 mmol) of C6 and 200 mL of ethyl acetate. The solution was cooled to −5° C. to −10° C. with methanol-ice bath. Then, the solution prepared from above procedure was slowly added (30 minutes). After the reaction was completed (monitored by HPLC). The solution was diluted with 100 mL of water and warmed to 10° C., and stirred for 20 minutes. The organic layer was washed sequentially with 3×100 mL of saturated sodium bicarbonate, 100 mL of brine. Added 374 mL of ethyl acetate, and distilled ethyl acetate under vacuum in house vacuum until the residue volume about 274 mL. Heated the solution >50° C., and added 822 mL of heptane while maintaining the temperature <50° C. Cooled the solution to 10° C., and seeded with Plant A11. Maintained the temperature of the suspension at 0-5° C. for 4 hours, then warmed to RT (24° C.) for 14 hours, cooled to −5° C. to −10° C. for 3 hours. The solid was filtered and washed with 100 mL of cold heptane/ethyl acetate (4/1 by volume) and dried to give 24.0 g of C8 in 63% yield. The pure C8: [α]_(D) ²⁵=−97.02 (c, 1.0, MeOH). 

1. A process for preparing a compound of the formula (VIII)

comprising step A: contacting a compound of the formula (I)

with a compound of the formula (II) Y—O—NH₂  (II) in the presence of a carboxy activating agent, in a suitable solvent under conditions suitable to form a compound of the formula (III)

followed by step B: contacting compound (III) with a compound of the formula (XIII) R′—SO₂—X′  (XIII) in the presence of a base in a suitable solvent, under conditions suitable to form a compound of the formula (IV)

followed by Step C: contacting compound (IV) with a base in a suitable solvent under conditions suitable to form a compound of the formula (V)

followed by Step D: contacting compound (V) with a compound of the formula (VI)

in a suitable solvent optionally in the presence of an activator under conditions suitable to form a compound of the formula (VII)

followed by Step E: contacting compound (VII) with a formylating agent in a suitable solvent under conditions suitable to form compound (VIII); wherein Y is a hydroxy protecting group; Each of R₂, R₃, R₄ and R₅, independently, is hydrogen or an aliphatic group; X is —CH₂; G is —OH or —O^(⊖)M^(⊕), wherein M is a metal or an ammonium moiety; R₁ is aryl or heteroaryl; X′ is halo; R′ is alkyl or aryl; and n is
 1. 2. The process of claim 1, followed by additional Step F which comprises contacting the compound of formula (VIII), wherein R₁ is heteroaryl having an N heteroatom, with an oxidizing agent to form the corresponding N-oxide derivative.
 3. The process of claim 1, followed by the additional step of removing the hydroxyl-protecting group by contacting compound (VIII) with a palladium catalyst to form the compound of formula (IX)

wherein R₁, R₂, R₃, R₄, R₅, X and n are as defined above.
 4. The process of claim 1, wherein each of R₂, R₃ and R₅ is hydrogen; R₄ is butyl; X is —CH₂—; n is 1; Y is benzyl or t-butyldimethylsilyl; and R₁ is of the formula

wherein R₆ and R₉ are hydrogen; R₇ is hydrogen or C₁₋₇alkyl; and R₈ is hydrogen, halogen or C₁₋₇alkyl.
 5. The process of claim 4, wherein R₇ is hydrogen; and R₈ is fluoro.
 6. The process of claim 4, wherein R₇ is C₁₋₇ alkyl; and R₈ is hydrogen.
 7. The process of claim 1, wherein R₁ is of the formula (XIa)

wherein R₆, R₇ and R₉ are hydrogen; and R₈ is halogen or C₁₋₇alkyl.
 8. The process of claim 7, wherein R₈ is fluoro.
 9. The process of claim 1, carried out at a temperature of about 0° C. to about 80° C., a pH of about 2 to about 12, and in one or more solvents selected from the group consisting of dioxane, methylene chloride, dichloromethane, toluene, acetone, methyl ethyl ketone, THF, isopropyl acetate, DMF and an alcohol. 